We now expand these data by reporting the first example of a secondary mutation, p.T910A, in the PARP1 HD that occurred in a patient whose disease progressed after 10 months of olaparib treatment, and protein structure modeling analyses supported a mechanism of olaparib resistance in which the p.T910A allele restores PARP1 activity in the presence of the drug by disabling HD-mediated autoinhibition. Here, PARP1 is linked to Huntington disease.